TITLE MULTIVALENT TICK-MICROBE TARGETED LYME DISEASE VACCINES PROJECT SUMMARY/ABSTRACT Lyme disease remains a prevalent tick-borne infection in many parts of the world. In the United States alone, there are over 300,000 new cases occurring each year. The infection is caused by Borrelia burgdorferi sensu lato, which is a group of atypical extracellular bacterial pathogens that survive in nature through a complex enzootic infection cycle involving ticks (belonging to the Ixodes scapularis complex) and an array of vertebrate hosts, most commonly wild rodents. Despite serious efforts to control the infection over the past several decades, the disease is still emerging around the globe, largely due to the absence of effective control measures against tick infestation, lack of human vaccines, difficulties in diagnosis, and clinical complications associated with treatments which use currently available antimicrobials. Specifically, several months after standard-care antibiotic therapy, a subset of patients can experience a series of persistent or relapsing symptoms, known as chronic Lyme disease or post-treatment Lyme disease syndrome, for which further treatment options remain unavailable. Therefore, the development of vaccines is highly warranted to combat Lyme disease. This project pursues our goals to develop a novel vaccination campaign that comprises selected antigens from both the Lyme disease pathogen and the tick vector, expressed from a well- established viral vector system. The approach incorporates a set of novel vaccine targets that are expressed on the microbial surface or towards the luminal surface of the tick gut. As highlighted in recently-published and preliminary data, immunization with these targets generates protective immunity in mammals. We will utilize highly efficient Rabies virus-based vaccine systems (RABV), which have broad applications as competent vaccine platforms for many infectious diseases and display remarkable safety profiles, as evidenced from their current use for human vaccination. The overall objective is embodied in three specific aims: 1) construction of a battery of recombinant replication-competent, replication-deficient RABVs and virions expressing B. burgdorferi and tick antigens, 2) characterization of vaccine constructs for long-term immunogenicity in murine models, and 3) identification of the most effective vaccine candidate(s) that modulate B. burgdorferi infection and generate protective immunity. We will also perform studies for understanding the mechanisms of the humoral and cellular immune responses associated with host protection. Overall, these studies will facilitate the design of safer, next generation vaccines to prevent the incidence of Lyme borreliosis. Moreover, the same approach may serve as a paradigm for combating other tick-borne infections. ! ! !